Genetic Variant RANBP3L:p.Leu223Ser (chr5-36260781-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145000.5(RANBP3L):c.668T>C(p.Leu223Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000152 in 1,319,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RANBP3L
NM_145000.5 missense, splice_region

Scores

Splicing: ADA: 0.2172

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54

Variant links:

Genes affected

RANBP3L (HGNC:26353): (RAN binding protein 3 like) Enables SMAD binding activity. Predicted to be involved in several processes, including mesenchymal cell differentiation involved in bone development; negative regulation of osteoblast differentiation; and positive regulation of myoblast differentiation. Predicted to be part of nuclear pore. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RANBP3L links:

LOC124900962 (HGNC:):

LOC124900962 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2996086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP3L	NM_145000.5 link	c.668T>C	p.Leu223Ser	missense_variant, splice_region_variant	Exon 8 of 14	ENST00000296604.8	NP_659437.3	Q86VV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RANBP3L	ENST00000296604.8 link	c.668T>C	p.Leu223Ser	missense_variant, splice_region_variant	Exon 8 of 14	1	NM_145000.5	ENSP00000296604.3	Q86VV4-1
RANBP3L	ENST00000502994.5 link	c.743T>C	p.Leu248Ser	missense_variant, splice_region_variant	Exon 9 of 15	2		ENSP00000421853.1	Q86VV4-3
RANBP3L	ENST00000515759.5 link	c.668T>C	p.Leu223Ser	missense_variant, splice_region_variant	Exon 8 of 10	2		ENSP00000421149.1	Q86VV4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000152

AC:

AN:

1319600

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

662664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30156

American (AMR)

AF:

0.00

AC:

AN:

42018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24722

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38758

South Asian (SAS)

AF:

0.00

AC:

AN:

80496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

990098

Other (OTH)

AF:

0.00

AC:

AN:

55488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.743T>C (p.L248S) alteration is located in exon 9 (coding exon 9) of the RANBP3L gene. This alteration results from a T to C substitution at nucleotide position 743, causing the leucine (L) at amino acid position 248 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Pathogenic

3.2

M;.;M

PhyloP100

4.5

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.063

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.31

MutPred

0.39

Gain of disorder (P = 0.0112);.;Gain of disorder (P = 0.0112);

MVP

0.52

MPC

0.17

ClinPred

0.99

GERP RS

4.1

Varity_R

0.35

gMVP

0.39

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.22

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-36260781-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over